IL-12 is a heterodimeric cytokine that is primarily produced by dendritic cells, macrophages and neutrophils and plays an essential role in the generation of type 1 immune responses and cell-mediated immunity (Brunda, J. Leukocyte Biol. 55:280-288 (1994); Scott and Trinchieri, Semin. Immunol. 9:285-291 (1997)). The results from several studies in a variety of animal models support the idea that rIL-12 has great promise as an adjuvant for prophylactic or therapeutic vaccines against infectious and metastatic diseases (Rodolfo and Colombo, Methods 19:114-120 (1999); Scott and Trinchieri, Semin. Immunol. 9:285-291 (1997)). Recently, it was reported that rIL-12 has the potential to serve as an adjuvant for natural F protein of RSV (Hancock et al. Viral Immunol. 13:57-72 (2000)). In BALB/c mice, the results suggested that rIL-12 enhanced the capacity of F protein, when adsorbed to aluminum hydroxide adjuvant (F/AIOH), to elicit T cell responses that were more balanced and not polarized towards a type 2 phenotype. However, co-formulation with rIL-12 did not completely regulate all type 2 responses elicited by F/AIOH. That is, upon challenge of mice primed with F/AIOH plus rIL-12, IL-5-dependent pulmonary eosinophilia was still observed. Furthermore, the data from recent phase I clinical trials (Atkins et al. Clin. Cancer Res. 3:409-417 (1997)) also suggest that high doses of rIL-12 may be too reactogenic for use in routine vaccination.
The ability of the highly purified saponin QS-21 (Kensil et al., J. Immunol. 146:431-437 (1991)) to improve the quality and quantity of immune responses to F protein has been reported (Hancock et al., Vaccine 13:391-400 (1995); Hancock et al., J. Virol. 70:7783-7791 (1996)). Compared to F/AIOH, vaccination of naïve mice with F/QS-21 resulted in the generation of augmented serum neutralizing titers that were associated with a shift in F protein-specific Ig production from the predominant G1 to G2a subclass. Upon challenge there was also an increase antigen dependent killer cell activity mediated by MHC class I restricted CD8+T cells and protein-specific antibody secreting cells in the lungs. Importantly, there was a significant reduction in IL-5-dependent pulmonary eosinophilia. However, clinical data has implied that QS-21 in this formulation was associated with local acute toxicity immediately after injection.